Man and many other organisms possess internal cellular mechanisms which are manifested as daily (circadian) rhythms. Biological rhythmicity is of importance with regard to the fundamental cellular processes responsible and how they may relate to cell cycles and cell proliferation. In both psychiatry and medicine it is known that circadian rhythmicity is involved in the timing of bodily functions, work-rest cycles, jet-lag, sleep, drug tolerance and drug efficacy. This research program is concerned with the elucidation of the basic cellular and molecular mechanisms involved in circadian rhythmicity. Our studies will utilize the unicellular dinoflagellate, Gonyaulax. We will test the postulate that the circadian clock mechanism is the same as a fundamental cell cycle clock, the cellular mechanism ultimately responsible for cell division. To test this hypothesis we will (1) examine the effects of drugs and inhibitors on the two systems, (2) compare rhythms of bioluminescence with time of cell division and time of key molecular events associated with the cell cycle both in cultures and in single isolated cells. In this work we will attempt to find out if, when circadian cells are dividing slowly, they nevertheless experience multiple fundamental cell cycle rounds. A second approach to the problem will involve the study of enzymes whose activities are controlled by the circadian mechanism. By using specific antibodies we will determine the specific activity of such enzymes as a function of time of day. On the assumption (from preliminary results) that the amount of one such enzyme (luciferase) varies with time of day, we plan to determine whether this change is due to differences in the rate of synthesis of luciferase, or its degradation, or both, by means of measurement of in vitro luciferase synthesis. It has also been proposed that the basic clock mechanism involves a c-AMP mediated mechanism: we have experimental evidence that this is not so in Gonyaulax, and we will further test this conclusion by measuring the intracellular c-AMP as a function of time of day in the presence and absence of methyl xanthines.